Throughout this application, various references are cited to describe more fully the state of the art to which this invention pertains. The disclosure of these references are hereby incorporated by reference into the present disclosure.
Acid labile H+K+-ATPase inhibitors, known as gastric proton pump inhibitors (PPI), are known and include the generic compounds such as omeprazole, lansoprazole, pantoprazole, pariprazole, rabeprazole and leminoprazole as disclosed for example in U.S. Pat. Nos. 4,045,563; 4,255,431; 4,628,098; 4,686,230; 4,758,579; 4,965,269; 5,021,433; 5,430,042 5,045,552 and 5,708,017. In general, the proton pump inhibitors of gastric acid secretion work by undergoing a rearrangement to form a thiophilic species which then covalently binds to gastric H+K+ATPase, the enzyme involved in the final step of proton production in the parietal cells, and thereby inhibits the enzyme.
Proton pump inhibitor compounds are useful for inhibiting gastric acid secretion in mammals and man and are used for prevention and treatment of gastric acid related diseases such as reflux esophagitis, gastritis, duodenitis, gastric ulcer and duodenal ulcer. Furthermore, they may be used for treatment of other gastrointestinal disorders where gastric acid inhibitory effect is desirable e.g. in patients on NSAID therapy, in patients with Non Ulcer Dyspepsia, in patients with symptomatic gastro-esophageal reflux disease, and in patients with gastrinomas. They may also be used in patients in intensive care situations, in patients with acute upper gastrointestinal bleeding, pre- and postoperatively to prevent acid aspiration of gastric add and to prevent and treat stress ulceration. Further, they may be useful in the treatment of psoriasis as well as in the treatment of Helicobacter infections and diseases related to these.
Proton pump inhibitor compounds are susceptible to degradation or transformation in acidic media. The degradation is catalyzed by acidic compounds and is more stabilized in mixtures with alkaline compounds. The stability of proton pump inhibitor compounds may also be affected by moisture, heat, organic solvents and to some degree by light. For example, proton pump inhibitor compounds such as pyridyl methyl sulfinyl benzimidazoles (having a pKa of 4.0 to 5.0) have a mechanism of action requiring accumulation in the acidic space of the parietal cell (secretory canaliculus, pH ca. 1.0) followed by subsequent hydrogen ion catalyzed conversion to the reactive thiophilic species that is capable of inhibiting the gastric ATPase enzyme resulting in effective inhibition of gastric secretion. Due to this mechanism this compound requires specialized gastro protection to remain active for duodenal absorption. For this reason, and due to sensitivity to degradation in the acid milieu of the stomach, oral formulations of proton pump inhibitor compounds are usually enteric coated. The need for enteric coating is a shortcoming because enteric coatings are expensive to provide and pH sensitive. Furthermore, the use of enteric coating means that the compound is not being released for absorption in the stomach. Enteric coating layers are known and disclosed for example in U.S. Pat. Nos. 4,853,230, 6,479,075 and 6,296,876.
U.S. Pat. No. 5,753,265 discloses an enteric coating layered multiple unit tablet that disperses into a multitude of small units in the stomach upon administration. Many different types of multiple unit dosage forms are known in the prior art. Usually this type of formulation is requested for controlled release formulations, such as sustained release formulations. Typically, the multiple unit formulation may be a tablet which disintegrates in the stomach to make available a multitude of coated units, or pellets filled in a capsule as is disclosed in EP 0 080 341 and U.S. Pat. No. 4,853,230. However, these do not allow for delivery of the proton pump inhibitor compound throughout the gastrointestinal tract (GIT).
U.S. Pat. No. 4,927,640 discloses a controlled release dosage form that releases the active substance by diffusion through a membrane. The dosage form is a multiple-unit system containing small inert cores coated with active substance and a release controlling polymeric membrane. Other examples of controlled release dosage forms are, for example, described in Aulton M. E. (Churchill Livingstone Ed.), Pharmaceutics: The science of dosage form design (1988), p. 316-321. These dosage forms do not sufficiently address the stability issues of the proton pump inhibitor compounds during transit in the gastrointestinal tract.
In practice, problems also arise when enteric coating layered pellets containing acid labile substances, such as proton pump inhibitor compounds, are compressed into tablets. If the enteric coating layer does not withstand the compression of the pellets into a tablet, the susceptible active substance will be destroyed by penetrating acidic gastric juice, i.e. the acid resistance of the enteric coating layer of the pellets will not be sufficient in the tablet after compression. Further, controlled release tablets from enteric coated particles are described in the article: Drugs Made In Germany, 37 No. 2 (1994), p. 53. This reference teaches a combination of methacrylic acid copolymer (L30D-55) and a copolymer of ethyl acrylate and methyl methacrylate (NE30D) suitable as a coating polymer for enteric coated particles compressed into tablets. However, the acid resistance of the pellets compressed into tablets is low.
U.S. Pat. No. 6,183,776 discloses an oral pharmaceutical dosage form comprising an acid susceptible proton pump inhibitor together with an antacid agent or an alginate in a fixed formulation, wherein the proton pump inhibitor is protected by an enteric coating layer and an optional separating layer is present between the proton pump inhibitor and the enteric coating. The fixed formulation is in the form of a multi-layered tablet, sachets or multiple unit tableted dosage form.
The prior art also describes fixed formulations in the form of multiple unit tablets with alkalinizing agents. These multiple unit dosage forms are not the most preferred because the enteric coated proton pump inhibitor is dumped only in the stomach due to the presence of the alkalinizing agent, where the drug is rapidly absorbed and has a short half life.
Acid secretion is necessary for the efficacy of proton pump inhibitor compounds because of the requirement for accumulation in the acid space of the parietal cell. Typical plasma half life of proton pump inhibitor compounds and formulations is only between 60 to 90 minutes. As not all acid pumps are active at any one time, rather only about 75% are active on the average during the time the drug is present in the blood following oral administration, in a currently used once-a-day oral administration therapy the maximum inhibition of stimulated acid output is approximately 66%. This is due to a combination of the short plasma half-life of the proton pump inhibitor compound, to the limited number of acid pumps active during presentation of the compound, and to the turn over of acid pumps. Furthermore, in current therapies it is not possible to control night-time acid secretion by an evening therapy of oral administration because the compound is dissipated from the plasma by the time acid secretion is established after midnight.
The ideal target for healing in acid related diseases and for treatment of H. pylori infection (in conjunction with antibiotics), as well as for relief of symptoms of non-ulcer dyspepsia, would be full inhibition of acid secretion. With the currently used proton pump inhibitor formulations, this is achieved only by intravenous infusion. In the case of the drug omeprazole, intravenous infusion of 8 mg per hour is required.
Clearly, there is a need in the art for a formulation of a proton type inhibitor compound, which can attain or approach full inhibition of acid secretion through oral therapy. There is a demand for the development of a novel proton pump inhibitor formulation that provides good chemical stability and more precise control of the release of the proton pump inhibitor compound within the gastrointestinal environment.